Imaging of axial spondyloarthritis including ankylosing spondylitis

Imaging of axial spondyloarthritis including ankylosing spondylitis ACR 2012 Prof. Dr. med. J. Braun Rheumazentrum Ruhrgebiet, Herne Ruhr-Universität Bochum Germany

Modified New York Criteria 1984 for Diagnosis/Classification of Ankylosing Spondylitis Clinical Criteria inflammatory back pain (Calin 1977) reduced spinal mobility in 2 planes ( < 3 cm) reduced thoracic excursion (< 3cm) Radiologic Criterium Sacroiliitis > grade II bilat. or > grade II unilat. No role for syndesmophytes > 95% of AS patients have definite changes in the SI joints van der Linden et al. A&R 1984

ASAS Classification Criteria for Axial SpA in patients with 3 months chronic back pain and age at onset < 45 years Sacroiliitis on imaging plus 1 SpA feature SpA features IBP arthritis enthesitis uveitis dactylitis psoriasis Crohn s/colitis Good response to NSAIDs Family history for SpA HLA-B27 elevated CRP OR HLA-B27 plus 2 other SpA features Sacroiliitis on imaging Inflammation on MRI highly compatible with sacroiliitis or Definite radiographic sacroiliitis according to mod. NY criteria Validation study in 649 patients with back pain Sensitivity 82.9% Specificity 84.4% Imaging obligatory Sensitivity 66.2% Specificity 97.3% Rudwaleit et al. Ann Rheum Dis 2009

Axial spondyloarthritis including AS (inflammatory) back pain Stage 1 Stage 2 Stage 3 Sacroiliitis (MRI) Radiographic changes due to sacroiliitis (NY criteria) Radiographic changes due to spondylitis (syndesmophytes) Spondylitis (MRI) non-radiographic axspa Ankylosing spondylitis

Defining active sacroiliitis and spondylitis on MRI - a consensual approach by the ASAS/OMERACT MRI group Active inflammatory lesions such as bone marrow oedema (BMO)/ osteitis, synovitis, enthesitis and capsulitis associated with SpA can be detected by MRI. Among these, the clear presence of bone marrow edema / osteitis was considered essential for defining active sacroiliitis and spondylits (> 3 lesions). Structural damage lesions such as sclerosis, erosions, fat deposition and ankylosis can also be detected by MRI. At present, however, the exact place of structural damage lesions for diagnosis and classification is less clear, particularly if these findings are minor. The ASAS group approved these proposals by voting. Rudwaleit M et al. Ann Rheum Dis 2009 Oct;68(10):1520-7; Hermann KG et al. Ann Rheum Dis 2012

Extended inflammation in the sacroiliac joints predicts development to AS (MRI and HLA-B27) sacroiliitis with large bone marrow edema Sensitivity and specificity 77 % Positive predictive value 60-80 % Negative predicitive value > 80% No predictive value of bilateral involvement moderate sacroiliitis Bennett A et al. Arthritis Rheum 2008

Does axial SpA always start in the sacroiliac joints? no, but yes in the majority of cases 50% spinal inflammation in patients with axspa < 5 years disease duration SPARCC, cut-off? 5-10% in other studies van der Heijde D et al. Ability I. EULAR 2012.

The likelihood of a positive MRI of the sacroiliac joints in patients with early IBP (< 2 years duration) n = 68 patients 38% male mean age 35 years 46 % HLA B27+ 24 % psoriasis 15 % IBD 15 % AAU 20 % structural changes in the SI joints at baseline (n=14) 35 % positive MRI at baseline (n=24) Prediction of positive MRI by HLA B27 and male gender - in MRI-positive patients 88 % - in MRI-negative patients 27 % - 23 MRI follow ups - 30 % had a negative MRI on follow up In an HLA B27- patient with a negative MRI at baseline the likelihood of a positive mri in the future is < 5 % Heuft-Doorenbusch L et al. Ann Rheum Dis 2006; 65: 804-808 van Onna M et al. Ann Rheum Dis 2011; 70: 1981-1985

Chronic changes in the SI joints (MRI) erosion fat Rheumatologist training to recognize lesions on T1-weighted MRI enhances diagnostic utility of MRI in patients with ankylosing spondylitis Maksymowych WP, et al., Arthritis Rheum 2009; 60 S200; #540

Comparison of conventional X-ray with CT using SASSS for AS patients CT proved more sensitive in the detection of sclerosis and syndesmophytes (3D-reconstruction) no significant difference for erosions and squaring higher SASSS-Score using CT in the lumbar spine Lee S-H, et al., Arthritis Rheum 2009; 60 S198; #534

CT scanning facilitates the diagnosis of sacroiliitis in patients with suspected spondylarthritis: results of a prospective multicenter French cohort study. METHODS: The Echography in SpA French cohort consists of 489 patients with suspected SpA. Pelvic CT scanning was performed if sacroiliitis on radiography was considered uncertain or if patients presented with buttock pain duration of > 6 months. A set of 100 paired radiographs and CT scans was read in a blinded manner by 2 radiologists. One of them read the 173 available pairs of radiographs and CT scans. RESULTS: After training, interreader reliability was moderate for sacroiliitis grading on radiographs (k = 0.59), excellent on CT scans (k = 0.91), and excellent for ascertaining sacroiliitis on both radiographs (k = 1) and CT scans (k = 0.96). The first and second readers considered the quality of imaging to be excellent in 66% and 67%, respectively, of the radiographs (k = 0.88) and in 93% and 92%, respectively, of the CT scans (k = 0.93). Concordance between radiographs and CT scans was low for sacroiliitis grading (k = 0.08) or ascertainment (k = 0.16). Definite sacroiliitis was ascertained on radiographs in 6 patients (3.5%) (confirmed by CT scans in 4 patients) and on CT scans in 32 patients (18.5%). A history of uveitis was associated with definite sacroiliitis on radiographs (p = 0.04) and CT scans (p < 0.0001). CONCLUSION: Definite sacroiliitis was underestimated by radiography. CT scanning should facilitate the diagnosis of AS in patients with suspected SpA. Devauchelle-Pensec V et al. Arthritis Rheum. 2012 May;64(5):1412-9. Radiation exposure!

Fat accumulation and syndesmophytes in AS (MRI) The fatty Romanus lesion (FRL) a non-inflammatory spinal MRI lesion specific for axial SpA T1 T1 > 5 FRL have a LR of 12,6 for AS Benett A et al. Arthritis Rheum 2009; 60 S195; #526

Spinal inflammation lesions as detected by MRI in patients with early AS are more often observed in posterior spinal structures Patients with SpA and a short history of IBP (n = 11) had significantly more lesions in posterior spinal structures than in vertebral bodies: 90.9 vs 27.2%, respectively (P < 0.003). Isolated changes in posterior spinal structures were seen in 8 of these patients (72.7%). Bochkova AG, Levshakova AV, Bunchuk NV, Braun J. Rheumatology (Oxford). 2010 Jan 18

Does the site of MRI abnormalities match the site of recent-onset inflammatory back pain (IBP)? The DESIR cohort. OBJECTIVES: To assess whether the site of axial pain (thoracic spine, lumbar spine or buttock(s)) was associated with the site of MRI lesions in patients with recent IBP. METHODS: Cross-sectional study with 708 patients with possible SpA. Radiographs of the sacroiliac joints (SIJs) and MRI scans of the SIJs and thoracic and lumbar spine were obtained routinely. Associations between pain sites and sites of inflammatory and structural MRI changes were evaluated using separate multivariate logistic regressions. RESULTS: Of the 648 patients with complete data, 61% had thoracic pain, 91.6% lumbar pain and 79.2% buttock pain. MRI inflammation was seen in 19%, 21% and 46% of patients at the thoracic, lumbar and SIJ sites, respectively. By multivariate analysis, pain was significantly associated with MRI inflammation only at the same site (adjusted OR (aor)(thoracic) (pain) 1.71; 95% CI 1.09 to 2.67; p=0.02; aor(lumbar pain) 2.53; 95% CI 1.03 to 6.20; p=0.04; aor(buttock pain) 2.86; 95% CI 1.84 to 4.46; p<0.0001). Pain site was not significantly associated with the site of structural MRI changes, except for buttock pain and SIJ structural MRI changes (aor(buttock pain) 1.89; 95% CI 1.22 to 2.90; p=0.004). The association between pain site and site of MRI inflammation persisted in the subgroups with normal or doubtful SIJ radiographs or with ASAS criteria for axspa. CONCLUSIONS: The site of pain (thoracic spine, lumbar spine or buttock(s)) is associated with MRI inflammation at the same site in patients with recent IBP. Blachier M et al. Ann Rheum Dis. 2012 Aug 14 [Epub ahead of print]

Prognostic factors in AS (SpA) no agreement on severity (ASAS discussion) gender (male patients have more structural changes) x-rays (presence of one syndesmophyte predicts development of future syndesmopyhtes) degree of inflammatory sacroiliac lesions (MRI) elevated CRP smoking manual work hip involvement cervical spine involvement peripheral arthritis

Modified Stoke Ankylosing Spondylitis Spinal Score (msasss) (range 0-72) 1 1 2 2 C7 3 3 range 0-72 Creemers MCW et al. Ann Rheum Dis 2005;64:127-9

msasss change Radiographic progression of AS patients treated with celecoxib or another NSAID continuously or on demand 2-year progression in msasss (units) 8,0 4,0 0,0 Celecoxib or another NSAID for 2 years continuous or on demand Treatme nt s trategy continuous on demand 5 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 p=0.002 continuous on demand 1,7 0,4-4,0 1 reader, blind for therapy and date 0,00 0,25 0,50 0,75 1,00 Cum ulative probability 70% of patients treated with celecoxib mean difference of dose < 50 mg/day Wanders et al. Arthritis Rheum 2005;52:1756-65

Continuous NSAID use reverts the effects of inflammation on new bone formation in patients with ankylosing spondylitis The effect of CRP values Kroon F et al. Ann Rheum Dis 2012 April 25th

Objectives Determine whether infliximab (IFX)+naproxen (NPX) therapy is superior to NPX monotherapy in patients with active, moderate to severe axial SpA who were naïve to NSAIDs or had a submaximal dose of NSAIDs. Improvement of signs, symptoms, and function Reduction of active MRI inflammation of the spine and SI joints Part I analysis: Evaluate efficacy in each treatment group. Part II analysis: In patients who achieved ASAS partial remission in Part I, measure changes in response during follow-up with either NPX or no treatment. ASAS=Assessment in Ankylosing Spondylitis; SI=sacroiliac.

INFAST Study Design Screening /Washout Part I: Treatment Phase 2:1 randomization IV infusions: weeks 0, 2, 6, 12, 18, and 24 IFX (5 mg/kg)+npx (1000 mg/d) Part II: Follow-up Phase Only patients with ASAS partial remission at week 28 Discontinue IFX 1:1 randomization NPX (1000 mg/d) PBO+NPX (1000 mg/d) No Treatment Patients without ASAS partial remission discontinue study Screening MRI Baseline Week 28 Week 52 MRI MRI at Week 52 or ET ET=early termination; IFX=infliximab; IV=intravenous; NPX=Naproxen; PBO=placebo.

Key Patient Inclusion Criteria 18 48 years of age NSAID-naïve or submaximal dose of NSAIDs Axial SpA according to ASAS classification criteria with symptom duration < 3 years Signs of active sacroiliitis on MRI Active disease at screening and baseline, defined as total back pain evaluation of 40 mm and BASDAI score of 40 mm (on VAS scales of 0 to 100 mm) BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; VAS=visual analog scale.

Baseline Characteristics Characteristic IFX+NPX (N=105) a PBO+NPX (N=51) b Gender, male 69% 78% Age, years, mean (SD) 31.7 (8.51) 30.7 (7.34) Years since symptom onset, mean (SD) 1.76 (0.896) 1.91 (1.439) Number of SpA manifestations (SD) 3.8 (1.4) 4.0 (1.23) Patients with readable MRIs and active lesions at screening Spine SI joint Spine or SI joint 59% 88% 91% 59% 90% 94% SI x-ray findings (bilateral grade 2 or unilateral grade 3), n (%) 61 (57.5) 33 (63.5) BASDAI (100-mm VAS), mean (SD) 64.4 (15.37) 63.0 (15.43) HLA-B27 positive status, n (%) 87 (82.1) 47 (90.4) BASFI (100-mm VAS), mean (SD) 53.1 (21.92) 54.0 (22.26) BASFI=Bath Ankylosing Spondylitis Functional Index; HLA=human leukocyte antigen. a For disease characteristics, N=106. b For disease characteristics, N=52.

Patients With ASAS Partial Remission, % Percentage of Patients with ASAS Partial Remission in Part I Primary endpoint P=0.0018 P=0.0032 P=0.0021 P=0.0251

Clinical and MRI Outcomes in Part I Clinical Outcomes from Baseline to Week 28 IFX+NPX (N=105) PBO+NPX (N=51) Clinical Outcome Baseline, mean Week 28, mean Change, mean Baseline, mean Week 28, mean Change, mean BASDAI (100-mm VAS) 64.4 18.0 46.6 63.0 32.2 30.2 BASFI (100-mm VAS) 53.1 17.1 35.0 54.0 26.9 28.5 CRP (mg/dl) 2.02 0.91 1.24 1.65 1.15 0.55 Berlin MRI Scores from Baseline to Week 28 IFX+NPX (N=105) PBO+NPX (N=51) MRI Outcome n Baseline, mean Week 28, mean n Baseline, mean Week 28, mean Spine score 98 2.9 0.5 47 4.2 1.5 SI joint score 97 5.6 1.3 47 6.6 3.0 CRP=C-reactive protein.

Patients With Complete Absence of MRI Lesions, % Percentage of Patients With Complete Absence of MRI Lesions at Week 28 100 90 80 70 60 50 40 30 20 10 0 p = 0.09 IFX+NPX (N=105) PBO+NPX (N=51) 60.0 45,1 p = 0.0013 p= 0.0004 27,6 18,1 5,9 0 Spine SI Joints Spine+SI Joints Location of Lesion

Presence/Absence of Inflammation in Patients with ASAS Partial Remission at Week 28 Inflammation on MRI Patients with ASAS Partial Remission IFX+NPX (n=63) n (%) PBO+NPX (n=18) n (%) Absent 20 (31.7) 1 (5.6) Present 43 (68.3) 17 (94.4)

Patients Enrolled in Part II Follow-up Study (Week 28 52) Patients were eligible for Part II if they achieved ASAS partial remission at Week 28. Clinical Status at Week 28 NPX (N=41) No Treatment (N=41) BASDAI (100 mm VAS), mean (SD) 7.1 (6.63) 6.2 (6.99) BASFI (100 mm VAS), mean (SD) 5.7 (6.03) 7.1 (10.01) CRP (mg/dl), mean (SD) 0.39 (0.786) 0.58 (0.747) No MRI inflammation, n/n a (%) 11/36 (30.6) 12/37 (32.4) In each of the randomized treatment groups in the ITT population in Part II: 31 patients were from the IFX+NPX group in Part I 9 patients were from the PBO+NPX group in Part I ITT=intent-to-treat. a N=patients with spine and SI joint MRI scores at Week 28.

Patients With ASAS Partial Remission, % ASAS Partial Remission During Part II p > 0.1, for all comparisons

Patients With Complete Absence of MRI Lesions, % Percentage of Patients With Complete Absence of MRI Lesions at Week 52 p > 0.05, all comparisons Location of Lesion

Change in Berlin MRI Scores in Part I and Part II for Patients Enrolled in Part II Worsening Part II Part II Change in Median Berlin MRI SI Joint Score a Part I 3.00 Part II Part II 1.50 1.75 Part I Part I Part I 2.75 Improvement IFX+NPX NPX (N=31) IFX+NPX No Tx (N=31) PBO+NPX NPX (N=9) PBO+NPX No Tx (N=9) Tx=treatment. a Change in Part I is the difference between the medians at baseline and Week 28. Change in Part II is the difference between the medians at Weeks 28 and 52.

Conclusions In Part I, patients with early, active, moderate to severe axial SpA who were treated with IFX+NPX had greater MRI improvement, and a greater percentage achieved MRI remission than patients treated with NPX alone. In Part II, no differences were observed in MRI measures for patients who received NPX vs no treatment. Efficacy results from Part II should be interpreted with caution because of the small number of patients. The safety profile for IFX+NPX was consistent with that of other anti-tnf biologics.

Radiographic progression in AS patients after 2 years of anti-tnf therapy in comparison to a historical cohort (OASIS) Etanercept 2 p > 0,05 Infliximab 1 p > 0,05 Etanercept OASIS all OASIS II Infliximab OASIS all OASIS II Adalimumab 3 p > 0,05 OASIS patients fulfilling the entry criteria for anti-tnf trials Adalimumab OASIS all OASIS II van der Heijde D et al. Arthritis Rheum 2008 May; 58(5):1324-31 van der Heijde D et al. Arthritis Rheum 2008 Oct; 58(10):3063-70 van der Heijde D et al. Arthritis Res Ther. 2009;11(4):R127

Radiographic progression after 4 years of anti-tnf - results from GO-RAISE Mean msasss change % patients with progression > 2 msasss units Braun J, ACR 2011; 423

Longterm structural effect of anti-tnf therapy with infliximab in patients with AS Although the patient numbers are relatively low and the nature of the historical cohort, we see no evidence for increased radiographic progression under continuous IFX. In contrast, it seems possible that long-term anti-tnf therapy may even delay the progression of radiographic damage (new bone formation). Baraliakos et al. Poster ACR 2011 (THU0497)

Clinical Efficacy and Safety of Continuous anti- TNF Therapy over a Decade in Patients with AS n=69 (n=42 at 5yrs, n=29 at 10yrs) IFX 5mg/kg q6w Disease status according to ASDAS No indication of a loss of efficacy. The most frequent reason for treatment discontinuation were AEs and pragmatic reasons. Lack of efficacy and infusion reactions contributed to only 15% of all drop outs (<10% of patients). Baraliakos et al. [poster]. EULAR 2012 THU0286.

Intended as medical information EASIC 37 European Ankylosing Spondylitis Infliximab Cohort: Long-Term efficacy over 5 years Completer analysis (n=76/89) At the end of EASIC: 78% pts had no arthritis and 85% no enthesitis Heldmann F et al. Clin Exp Rheumattol 2011

EASIC imaging substudy Baseline characteristics Baseline parameter (n=73 pat.) Age (years), mean SD BASDAI (0-10 units), mean SD BASFI (0-10 units), mean SD BASMI (0-10 units), mean SD CRP (mg/dl), mean SD Value 40.5 10.5 6.5 1.4 5.9 1.6 4.1 1.7 2.9 2.3 Disease duration (years), mean SD 10 8.4 HLA B27+ (%) 61 (83.6%) Male (%) 63 (86.3%) Baraliakos X et al. EULAR 2012

EASIC imaging substudy Baseline characteristics n VEs at baseline 1800 1600 1400 1200 1000 800 600 400 200 0 1526 All VEs 1437 1445 94.2% 1 2 VEs without syndesmophytes Baralaikos X et al. EULAR 2012

Course of different spinal lesions in EASIC % VE-edges Baraliakos X et al. EULAR 2012

Development of new syndesmophytes in relation to the MRI finding at baseline before the start of anti-tnf therapy 5,7% INF+ 6,7% 57,1% 14,3% 22,9% FD+ INF+ and FD+ INF- and FD- 58,3% 18,3% 16,7% 2 years 5 years n=35 new syndesmophytes n=61 new syndesmophytes Baraliakos X et al. EULAR 2012

Development of new syndesmophytes in relation to the MRI finding at baseline before the start of anti-tnf therapy Baseline Anti-TNF therapy 2 years Relative Risk 5 years Type 1: INF 71% INF - 0.8 29% Type 2: FD 1.5 FD + Synd+ Type 3: INF+ and FD+ 3.3 Type 4: INF- and FD- 2.4 no INF, no FD at BL and 2y, no Synd = 1 Baraliakos X et al. ACR 2012

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